Summary/Abstract Chronic stress has been shown to negatively impact mental health and can precipitate depression and anxiety. Currently available medications to treat these disorders are only effective in approximately half of patients. It is thought that these medications don't adequately target the range of underlying etiologies that define stress disorders. Recent evidence suggests that dysregulation of peripheral inflammatory signaling in humans is linked to mood and anxiety disorders. Using an animal model of repeated social defeat stress (RSDS) in which c57BL/6J mice are repeatedly attacked by a large CD1 aggressor mouse, we find similar dysregulation of inflammatory signaling, which we have now shown is causally linked to depression and anxiety-like behavioral responses. Targeting of peripheral inflammatory signaling is sufficient to reverse the maladaptive behavioral responses to stress through alterations of plasticity directly within the brain. Interestingly, we recently found that botanical supplements promote resilience to social stress, possibly by reducing systemic inflammation and preventing maladaptive plasticity in the CNS. Thus, in this application, we will define the role of phenolic compounds in promoting psychological resilience and test the functional mechanisms responsible. Our goal is to identify alternative therapeutic approaches to ultimately promote resilience to stress disorders in humans.